Modifier system for compositions containing layered double hydroxide

ABSTRACT

The invention relates to a composition comprising: i) one or more LDH-active anion materials comprising an LDH matrix intercalated with one or more active anions, and ii) a modifier system comprising a) one or more surfactants, in combination with b) one or more compounds having the generic formula MA, where M comprises one or more positively charged ions and A comprises one or more negatively charged counter ions.

FIELD OF THE INVENTION

The present invention relates to compositions which contain i) layereddouble hydroxide (LDH) materials intercalated with one or more activeanions (LDH-active anion materials), together with ii) a modifier systemfor controlling the release of the active anion from the LDH-activeanion material and for controlling the solubility of the released activeanion in acidic media. The present invention particularly relates tocompositions in which the active anion in the LDH-active anion materialis a pharmaceutically and/or a nutraceutically active anion, and to theuse of such compositions in formulations suitable for pharmaceuticaland/or nutraceutical applications.

BACKGROUND OF THE INVENTION

A review of layered double hydroxides (LDHs) is given in Chemistry inBritain, September 1997, pages 59 to 62, and briefly, these materialsare either mixed hydroxides of monovalent and trivalent metals or mixedhydroxides of divalent and trivalent metals, having an excess ofpositive charge that is balanced by interlayer anions. Such materialscan be represented either by:

[M^(I) _((1-x))M^(III) _(x)(OH)₂]^(n+)A^(z−) _(n/z).yH₂O or

[M^(II) _((1-x))M^(III) _(x)(OH)₂]^(x+)A^(z−) _(x/z).yH₂O

where M^(I), M^(II) and M^(III) are mono-, di- and trivalent metalcations respectively, that occupy octahedral positions in hydroxidelayers; A^(z−) is an interlayer charge-compensating anion; z is aninteger; n=2x−1; x is less than 1; and y is >0.

The methods used in the manufacture of LDH materials are well documentedand can include ion exchange, co-precipitation, rehydration, secondaryintercalation, re-coprecipitation, and templated synthesis methods, seefor example He et al., Struct. Bond, 2006, 119, p. 89-119. There arealso different methods for preparing LDH materials intercalated withlarge active anions for example pharmaceutically active molecules andbiomolecule, as described in EP0987328(B1), WO2010/089691A1,CN101597474B and EP0550415 A2.

In all end-use applications involving LDH-active anion materials it isimportant to control release of the intercalated active anion from thelayers of the LDH structure; firstly, to exert control over the onsetand extent of efficacy of the active anion (especially relevant when theactive anion is pharmaceutically and/or nutraceutically active), andsecondly by controlling active anion release it is possible to improvethe safety, toxicity, ease of use and/or ease of handling of theLDH-active anion material.

In their earlier patent application PCT/GB2013/052554, the Applicantdescribes a process for making improved controlled-release LDH-activeanion materials which are able to retain substantially all of the activeanion within the LDH matrix whilst in the absence of ion exchangeconditions and/or under conditions where the pH is >4. These improvedLDH-active anion materials are particularly useful in orally deliveredformulations which call for the need to taste-mask an active anion thatis poor-tasting, or which causes burn, irritation or some otherunacceptable sensation, within the mouth, buccal cavity or larynx; thepH of the mouth is pH 6.2-7.6, and the improved LDH-active anionmaterials are designed to retain the active anion within the LDHstructure until after swallowing. Non-standard tablet formulations suchas chewable tablets, orally disintegrating tablets, orallydisintegrating granules and lozenges which are sucked or chewed areeasier for a patient to take than dry tablets, but since the LDH-activeanion will remain in the mouth for a few minutes before with tastemasking ability in order to reduce non-compliance by patients,particularly within paediatrics patient groups.

As well as controlling the release of the active anion in the mouth, itis also important to control the release and solubility of the activeanion from the LDH lattice when the LDH-active anion material enters thegastrointestinal tract.

EP 1341556(B1) teaches controlling or modifying the release of apharmaceutically active compound from a drug delivery system comprisingLDH materials intercalated with pharmaceutically-active anioniccompounds by incorporating a buffer into the formulation, oralternatively, by incorporating an anion-containing non-toxic compound.In use, the anion in the non-toxic compound is described aspreferentially displacing the pharmaceutically-active compound fromwithin the layers of the LDH. The non-toxic compounds preferred in thisprior art contain carbonate or hydrogen carbonate anions, such as CaCO₃,Ca(HCO₃)₂, MgCO₃ and Mg(HCO₃)₂. However, the Applicant has found thatthese non-toxic compounds produce only a slight increase in thesolubility in an acid medium of an acid insoluble active anion, such asibuprofen, when it is displaced from within the layers of the LDH-activeanion material. At this low solubility level it is highly unlikely thatit will be possible to achieve a pharmacokinetic profile comparable withthat obtained for the Ibuprofen free acid. Furthermore, contrary to theteachings in EP1341556(B1), the Applicant has evidence to indicate thatmetal carbonates do not promote much more active anion to be releasedfrom within the layers of the LDH matrix, than the amount which isreleased when a metal carbonate is not present.

As discussed by B. S. Sekhon in J. Pharmaceutical Technology Researchand Management, vol. 1 2013, 11-36: “Surfactants: Pharmaceutical andMedicinal Aspects”, surfactants are known to be components of manypharmaceutical products, for example i) to solubilise hydrophobic drugsin aqueous media, ii) as components of emulsions, iii) as surfactantself-assembly vehicles for oral and transdermal drug delivery, iv) asplasticisers in semisolid delivery systems and v) as agents to improvedrug absorption and penetration. Non-ionic surfactants such as ethers offatty alcohols are most commonly used in pharmaceuticals and serve asemulsifiers, wetting agents, solubilisers and dispersants. Further, D.Ramya Devi et al have compiled a review of the different attributes ofpoloxamer and its application in drug delivery in J. Pharm. Sci. & Res.Vol. 5(8), 2013, 159-165: “Poloxamer: A Novel Functional Molecule ForDrug Delivery and Gene Therapy”.

However, a research paper by P. Dewland et al, BMC Clinical Pharmacology2009, 9:19: “Bioavailability of ibuprofen following oral administrationof standard ibuprofen, sodium ibuprofen or ibuprofen acid incorporatingpoloxamer in healthy volunteers” concludes that poloxamer 407 surfactantis ineffective to enhance the dissolution and bioavailability of poorlywater soluble drugs, including ibuprofen.

Moreover, although several other studies report an increase in thesolubility of ibuprofen in acidic media as a result of the presence of apoloxamer 407 or 188 (non-ionic surfactants), this is disclosed as onlybeing possible when the two ingredients are in the form of a binarysolid dispersion, for example, R. P Dugar et al “Preparation andCharacterization of ibuprofen-Poloxamer 407” in AAPS PharmSciTech 2016Jan. 27 [Epub ahead of print], and M. Newa et al “Preparation,characterization and in vivo evaluation of ibuprofen binary soliddispersions with poloxamer 188”, International Journal of Pharmaceutics,Volume 343, Issues 1-2, 1 Oct. 2007, Pages 228-237. Further, theenhanced ibuprofen solubility is reported in these papers to be due tothe formation of eutectics between the ibuprofen and the poloxamer,rather than due to the presence of the surfactant per se. The loss ofibuprofen crystallinity in the fused ibuprofen/poloxamer mixture wasconfirmed by XRPD, and is disclosed to be the principle cause of theincreased solubility.

Meanwhile, Hoo-Kyun Chi and Sung-Hyun Park report in the InternationalJournal of Pharmaceutics 321 (2006) 35-41: “The effects of surfactantson the dissolution profiles of poorly water-soluble acidic drugs”, thatthe dissolution of acidic drugs such as mefenamic acid, nimesulfide andibuprofen is substantially enhanced in a medium containingcetyltrimethylammonium bromide (CTAB), a cationic surfactant, ascompared against sodium lauryl sulfate (SLS), an anionic surfactant, orpolysorbate 80, a non-ionic surfactant.

Notwithstanding the prior art discussed above, there is a need 1) tocontrol the amount of active anion which is released from between thelayers of LDH in an LDH-active anion material, and also 2) to controlthe solubility of the released active anion in acidic media,particularly in the case of poorly water soluble active anions such asibuprofen. Controlling release to increase the amount of active anionreleased and increasing its solubility in the stomach may lead to fasterand increased absorption. Conversely, controlling release to reduce theamount released in the stomach may provide for slower absorption.

STATEMENT OF THE INVENTION

The aim of the present invention is to provide compositions whichcontain LDH-active anion materials and which enable the controlledrelease of the active anion from within the LDH layers, when in anacidic media designed to represent the conditions found in a fastedhuman stomach. Advantageously, the active anion is a pharmaceuticallyand/or nutraceutically active anion.

It is desirable that the compositions of the present invention controlthe release of the active anion by effecting either an increased or adecreased amount of active anion to be released from within the LDHlayers of an LDH-active anion material, relative to the amount releasedby the LDH-active anion alone, in an acidic media.

Another key goal of the present invention is to provide compositionswhich contain LDH-active anion materials and which enable the controlledsolubilisation of the active anion in acidic media.

Thus, a further aim is to provide compositions which contain LDH-activeanion materials and from which release of the active anion is controlledso as to either exhibit a fast and increased absorption of the activeanion in the gastrointestinal (GI) tract, or alternatively when areduced amount of active anion is released, to exhibit a slowerabsorption in the GI tract.

The present invention, therefore, provides a composition comprising: i)one or more LDH-active anion materials comprising an LDH matrixintercalated with one or more active anions, and ii) a modifier systemcomprising a) one or more surfactants, in combination with b) one ormore pharmaceutically acceptable salts having the generic formula MA,where M comprises or, in the alternative consists essentially of, one ormore positively charged ions (cations) and A comprises, or in thealternative consists essentially of, one or more negatively chargedcounter ions (anions).

As demonstrated in the specific examples below, the present inventionprovides a composition which contains a modifier system which is capableof 1) controlling the total amount of active anion released from the LDHmatrix under acidic conditions designed to represent the conditionsfound in a fasted human stomach, compared against the amount which isreleased when the modifier system is absent or when a surfactant is usedalone and 2) controlling the amount of active anion which is dissolvedin the acidic medium, compared against the amount which is dissolvedwhen a surfactant is used alone or when a metal salt is used alone orwhen the modifier system is absent. “Controlling the amount of activeanion which is dissolved in the acidic medium”, shall be interpreted tomean that a greater amount or a reduced amount of active anion may bedissolved in the acidic medium by the use of the modifier system of thepresent invention.

In one embodiment, the present invention provides a composition whichcontains a modifier system which is capable of promoting a significantincrease in the amount of active anion which is released and dissolvedin acidic media that is designed to represent the conditions found in afasted human stomach, when compared against the amount of active anionwhich is released and dissolved under comparable conditions in thepresence of either a surfactant alone or when in the presence of a metalsalt alone or when the modifier system is absent.

In another embodiment, the present invention provides a compositionwhich contains a modifier system which is capable of promoting asignificant reduction in the amount of active anion which is releasedand, at the same time, controlling the solubility of the active anionwhich is released in acidic media designed to represent the conditionsfound in a fasted human, compared against the amount of active anionwhich is released and dissolved under comparable conditions using asurfactant alone or a metal salt when used alone or when the modifiersystem is absent.

The Applicant has unexpectedly found that the combination of one or moresurfactants and one or more compounds having the generic formula MA usedin the modifier system of the present invention, shows synergisticactivity towards the release and solubility of an active anion in acidicmedia. Further, that this synergistic activity allows for the amount ofsurfactant to be reduced whilst maintaining the desired active anionrelease and solubility in acidic media. A reduction in the amount ofsurfactant is particularly advantageous for pharmaceutical andnutraceutical formulations where high levels of surfactant would beexpected to be unpalatable due to their soapy taste, and depending onthe surfactant used, could have an undesirable safety profile. Not onlythis, processing and formulation difficulties are also expected withhigh surfactant levels, for example it is likely to be difficult toensure that the ingredients are uniformly blended, and there may be anissue with forming tablets with the desired hardness.

The modifier system comprises any suitable surfactant, which ispreferably a pharmaceutically acceptable surfactant. Ideally themodifier system comprises one or more surfactants selected from:

-   -   1) anionic surfactants such as carboxylates: alkyl carboxylates        (e.g. fatty acid salts), carboxylate fluoro-surfactants;        sulfates: alkyl sulfates (e.g. sodium lauryl sulfate), alkyl        ether sulfates (e.g. sodium laureth sulfate); sulfonates:        docusates (e.g. dioctyl sodium sulfosuccinate), alkyl benzene        sulfonates; phosphate esters: alkyl aryl ether phosphates and        alkyl ether phosphates.    -   2) Zwitterionic (amphoteric) surfactants, which can be anionic,        cationic or non-ionic depending on the pH of the solution they        are in. Examples include: RN⁺H₂CH₂COO⁻, RN+(CH₃)₂CH₂CH₂SO₃ ⁻,        phospholipids such as phosphatidylcholine (lecithin).    -   3) Cationic surfactants which bear a positive charge for example        RN⁺H₃Cl⁻, RN⁺(CH₃)₃Cl⁻, diotadecyldimethylammonium chloride,        cetyl pyridinium chloride or benzalkonium chloride.    -   4) Non-ionic surfactants which are uncharged. Examples include:        polyol esters (e.g. glycol, glycerol esters, sorbitan and        sorbitan derivatives such as fatty acid esters of sorbitan        (Spans) and their ethoxylated derivatives (Tweens)),        polyoxyethylene esters and poloxamers.

The Applicant has found that anionic, zwitterionic and non-ionicsurfactants are particularly useful in the modifier system used in thecomposition of the present invention.

As used herein, the term “pharmaceutically acceptable” in relation toany of the ingredients or excipients included in the composition of thepresent invention is to be interpreted to mean that the ingredient orexcipient is permitted, e.g. by national regulatory agency approval, tobe used in pharmaceutical and/or nutraceutical formulations and/or anyother formulation for human or animal use and/or consumption.

Contrary to what would be expected from the known interactions between asurfactant and an active anion, as described above in relation tovarious prior art documents, the surfactants in the modifier system usedin the present invention do not merely act to increase the solubility ofthe active anion once it has been released. Indeed, as the resultspresented below in the specific examples demonstrate, although thepresence and chemical nature of a surfactant has a strong influence overthe amount of active anion which is released, not all surfactantspromote an increase in the solubility of the active anion.

Preferred surfactants to be used in the modifier system of the presentinvention, therefore, are those which intercalate and/or interact withthe LDH portion of the LDH-active anion material, either in addition to,or in the alternative to, controlling the solubility of the active anionfollowing its release from the LDH matrix. Anionic surfactants such assodium lauryl sulfate work very effectively and are believed to interactwith the cationic layers of the LDH, however, the Applicant hasunexpectedly found that poloxamers, which are non-ionic surfactants andlecithin, which is a zwitterionic surfactant, also interact in some waywith the LDH to cause the active anion to be released from the LDHmatrix, thus making these surfactants surprisingly highly effective inthe modifier system used in the compositions of the present invention.

The Applicant has also unexpectedly found that the choice of surfactantwill increase or decrease the amount of active anion being released fromthe LDH matrix, depending on the specific active anion being released.For example as described in the specific examples below, the Applicanthas conducted tests to determine the amount of active anion releasedfrom the LDH matrix after 15 minutes (to replicate normal in vivoactivity where material is retained in the stomach for about 15minutes). In the case of some LDH-active anion materials (e.g.LDH-ibuprofen, LDH-naproxen, LDH-diclofenac and LDH-ketorolac) amodifier system comprising at least one surfactant selected fromzwitterionic, anionic and non-ionic surfactants is found to lead to anincrease in the amount of active anion released, whereas use of acationic surfactant is found to reduce the amount of active anionreleased; in both cases compared against the amount of active anionreleased in the absence of the modifier system. By contrast, in the caseof other LDH-active anion materials (e.g. LDH-atorvastatin), azwitterionic surfactant (e.g. lecithin) is observed to decrease theamount of active anion released.

In pharmaceutical applications, irritant and cancer concerns arise inrespect of certain surfactants, for example sodium lauryl sulfate,therefore poloxamer and lecithin are especially preferred incompositions which are to be used in pharmaceutical and/or nutraceuticalformulations. Further, for taste masked formulations, poloxamer ispreferred since high levels of lecithin have an unpleasant odour.Poloxamer 407 is found to be particularly useful.

The compounds of the generic formula MA are preferably pharmaceuticallyacceptable salts which further preferably have a solubility of at least0.002 g/ml, and particularly preferably a solubility of at least 0.006g/ml, in the simulated stomach acid media (0.2% sodium chloride in 50 ml0.05M hydrochloric acid). Ideally the compounds MA comprise one or morecations, M, which are preferably one or more metal cations. These may beselected from mono-, di-, or tri-valent metals, and preferably selectedfrom alkali metals, alkaline earth metals and transition metals. Highlypreferred one or more cationic metals M are selected from iron,magnesium, aluminium, calcium, sodium, lithium, potassium, rubidium,caesium, barium, strontium, beryllium, manganese, cobalt, nickel,copper, silver, zinc, cadmium, titanium, lead, lanthanum and cerium; andone or more metals selected from calcium, magnesium, aluminium, lithium,sodium, potassium, iron and zinc are particularly preferred, and sodium,lithium, magnesium, calcium aluminium are the most preferred. In anotherembodiment the one or more cations, M, may comprise non-metallic cationsfor example ammonium, diethylamine or similar cations.

The compounds of the generic formula MA also comprise one or moreanionic counter ions, A. Any suitable anionic counter ion may be usedand preferably this is a pharmaceutically acceptable anionic counterion. Suitable one or more anionic counter ions are selected fromcarbonate, hydrogen carbonate, sulfate, hydroxide, oxide, chloride,bromide, fluoride, nitrate, dihydrogen phosphate, hydrogen phosphate,phosphate, acetate, maleate, citrate, mesylate, tartrate, gluconate,formate, malate, oxylate, succinate, tosylate, fumarate, pamoate,furoate, propionate, saccharate and thiocyanate anions. Particularlyuseful compounds of the generic formula MA contain at least onecarbonate and/or a hydrogen carbonate anion, and are preferably selectedfrom magnesium carbonate, magnesium hydrogen carbonate, calciumcarbonate, calcium hydrogen carbonate, sodium carbonate, sodium hydrogencarbonate, lithium carbonate and lithium hydrogen carbonate. Sodiumcarbonate and sodium hydrogen carbonate are especially preferred.

In the one or more LDH-active anion materials, the amount of LDH ispresent in an amount greater than 40% by weight of the LDH-active anionmaterial. An amount of LDH of 50% by weight of the LDH-active anionmaterial is ideal in the case of LDH-ibuprofen for example, but anamount of LDH greater than 60% by weight of the LDH-active anionmaterial may also be used, as can an amount of LDH of 70% by weight ofthe LDH-active anion material, for example when the active anionmaterial is atorvastatin.

As used herein, the term “active anion” includes any compound ormolecule that is anionic (i.e. a molecule with a negative charge) orfrom which an anion is generated, for example by dissolving the freeacid or salt form of a compound/molecule in aqueous solution. An anioniccompound/molecule is interpreted to be “active” in the sense that itproduces a chemical, physical, physiological, nutraceutical orpharmaceutical effect which is preferably recognised in an animal orhuman body. Suitable active anions may be simple anions or they may belarger and/or have more complex structures. Examples of compounds whichcontain an active anion may include additives used in medicaments, foodsupplements and vitamin supplements nutraceuticals and pharmaceuticals.

Preferred compounds which contain an active anion are those whichproduce a pharmaceutical effect, and these pharmaceutical compounds mayinclude the classes of NSAIDS, gaba-analogues, antibiotics, statins,angiotensin-converting enzyme (ACE) inhibitors, antihistamines, dopamineprecursors, anti-microbials, psychostimulants, prostaglandins,anti-depressants, anti-convulsants, coagulants, anti-cancer agents,immunosuppressants and laxatives. Preferred pharmaceutical compoundsinclude: ibuprofen, naproxen, ketorolac, diclofenac, indomethacin andatorvastatin, all in salt (e.g. sodium and calcium) and/or free acidform.

It is believed that the compositions of the present invention will beparticularly advantageous in relation to acidic pharmaceutical compoundsand/or those which are largely insoluble in acid media, for exampleibuprofen.

The modifier systems used in the compositions of the present inventionare able to control the amount of active anion released to be in therange 20% to 90% of the total amount of active anion present in theLDH-active anion material. As demonstrated in the specific examplesbelow, the amount of ibuprofen released from an LDH-ibuprofen materialis 65% of the total available in the absence of a modifier system and41% release in the presence of 300 mg sodium carbonate without asurfactant (400 mg LDH-ibuprofen equivalent to a 200 mg dose ofibuprofen) in acidic media. Also as demonstrated below, it is possibleto increase the solubility of the active anion (ibuprofen) which isreleased so that 57% is dissolved in acidic media (compared against 0.9%of the ibuprofen being dissolved in the absence of a modifier system and25% of the ibuprofen being dissolved in the presence of 300 mg sodiumcarbonate without a surfactant (400 mg LDH-ibuprofen equivalent to a 200mg dose of ibuprofen).

Surprisingly, the amount of the LDH matrix relative to the amount of theone or more compounds comprising the generic formula MA, as definedabove, is found to be highly influential in giving the flexibility inthe controlled release of the active anion from the LDH layers and alsoin increasing the solubility of the released active anion in acidicmedia, provided an amount of surfactant is also present. Preferably,weight ratio of the LDH matrix:the one or more compounds comprising thegeneric formula MA as defined above: the one or more surfactants, of2:0.1 to 4:0.1 to 4.

Specifically, when the modifier system contains an amount of a compoundof generic formula MA which is below a certain range, there is areduction in the amount of active anion that is released from theLDH-active anion material as compared against the amount released whenno compound of the generic formula MA is present. Thus, in a modifiersystem which is designed to decrease the amount of active anion releasedfrom the LDH matrix (compared against the amount which is released inthe absence of the one or more compounds of generic formula MA i.e. todecrease the active anion release to less than 40%), the preferredweight ratio of LDH matrix:the one or more compounds of the genericformula MA surfactant is 2:0.1 to 1:0.1 to 4.

On the other hand, where the modifier system is designed to increase theamount of active anion released from the LDH matrix (compared againstthe amount which is released when the one or more surfactant compoundsare present in the absence of the one or more compounds of the genericformula MA), the preferred weight ratio of LDH matrix:one or morecompounds comprising the generic formula MA:surfactant is 2:>1 to 4:0.1to 4, and further preferably 1:1:0.25 to 1.

An especially preferred composition of the present invention comprises amodifier system which comprises 1 part by weight of LDH matrix, at least0.5 parts by weight of one or more compounds of the generic formula MAand 1 part by weight of surfactant. An example of such a composition is:400 mg LDH-ibuprofen (contains 200 mg LDH), at least 100 mg sodiumcarbonate and 200 mg of one or more surfactants selected from sodiumlauryl sulfate, lecithin and poloxamer, i.e. the ingredients(LDH:MA:surfactant) in a ratio of 1:>0.5:1. A highly preferredcomposition comprises 400 mg LDH-ibuprofen (contains 200 mg LDH), 200 mgsodium carbonate and 200 mg of lecithin i.e. the ingredients (LDH:sodiumcarbonate lecithin) in a ratio of 1:1:1.

Advantageously, it has also been found that the amount of the one ormore surfactants can be decreased without compromising the increasedamount of active anion which is released or affecting the amount ofreleased active anion which is solubilised in acidic media. This can beachieved by adding more of the one or more compounds of the genericformula MA; for example a weight ratio of the LDH-active anionmatrix:one or more compounds of the generic formula MA:the one or moresurfactants, for such a scenario can be 2:>1:0.5 to <2.

In a further embodiment the present invention provides a compositionwhich comprises a modifier system which comprises a) a mixture of two ormore surfactants, as defined above, and b) a mixture of one or morecompounds of the generic formula MA, as defined above.

In an alternative embodiment the present invention provides acomposition which comprises a modifier system which comprises a) amixture of one or more surfactants, as defined above, and b) a mixtureof two or more compounds of the generic formula MA as defined above.

In yet another embodiment, the present invention provides a methodfor 1) controlling the total amount of active anion released from theLDH matrix under acidic conditions designed to represent the conditionsfound in a fasted human stomach, and 2) controlling amount of releasedactive anion which is dissolved in the acidic medium, the methodcomprising the step of forming a composition comprising: i) one or moreLDH-active anion materials comprising an LDH matrix intercalated withone or more active anions, and ii) a modifier system comprising a) oneor more surfactants, in combination with b) one or more compounds havingthe generic formula MA, preferably pharmaceutically acceptable salts,where M is a cation, preferably metal cation and A is an anionic counterion, wherein the amount of released one or more active anions which isdissolved in the acidic medium is controlled (preferably increased)relative to both the amount which is dissolved when the one or moresurfactants is used in the absence of the one or more compounds havingthe general formula MA and the amount which is dissolved when the one ormore compounds having the general formula MA is used in the absence ofthe one or more surfactants.

Any suitable method may be used to determine the % release of the activeanion and also the % solubility of the released active anion in an acidmedium. In one convenient method described below, % release and %solubility were both determined after 15 minutes, although a longer or ashorter time may be used if desired, 15 minutes was chosen because thisis the approximate time for gastric emptying in a fasted stomach. 0.05MHydrochloric acid was chosen as the acid medium as this is a reasonableapproximation of the acidity found in the human stomach, however, anyother suitable medium may be used instead.

The compositions of the present invention are useful in a wide range ofstorage, carrier and delivery system applications for pharmaceutical andnutraceutical applications, especially where it is required to controlthe release of the active anion. The compositions of the presentinvention advantageously allow for control of the release under the acidconditions of the fasted human stomach, of the active anion fromLDH-active anion materials which are highly resistant to leaching, forexample when substantially all of the active anion is retained withinthe LDH matrix whilst the absence of ion exchange conditions and/orunder conditions of above pH 4.

Therefore the present invention provides for the use of a composition asa carrier, a storage system and/or in a delivery system, saidcomposition comprising i) one or more LDH-active anion materials, andii) a modifier system comprising a) one or more surfactants, and b) oneor more compounds of the generic formula MA, wherein the one or moresurfactants and the one or more compounds of the generic formula MA aredefined above.

The present invention also provides for the use of the composition ofthe present invention in oral pharmaceutical and/or nutraceuticalapplications, and in a further aspect, the compositions of the presentinvention are for use in the preparation of pharmaceutical and/ornutraceutical formulations.

Therefore, the present invention provides a formulation comprising acomposition containing i) one or more LDH-active anion materials, andii) a modifier system comprising a) one or more surfactants, incombination with b) one or more compounds of the generic formula MA, asdefined above, selected from dry granules, tablets, caplets, orallydisintegrating tablets, orally disintegrating granules, lozenges, films,capsules, powders, effervescent formulations and buccal and sub-lingualformats.

Advantageously the formulation according to the present inventioncomprises a composition which allows for the control of release of theactive anion from the LDH-active anion material contained therein.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will now be described with reference to thefollowing figures in which:

FIG. 1 is a graph of geometric mean concentration against time tocompare the Brufen® single dose PK with that obtained for LDH-ibuprofen.

FIG. 2 is a graph of % solubility v the amount of sodium carbonate, forsodium lauryl sulfate (SLS) surfactant;

FIG. 3 is a graph of % solubility v the amount of sodium carbonate, forlecithin surfactant;

FIG. 4 is a graph of % solubility v the amount of sodium carbonate, forpoloxamer 407 surfactant;

FIG. 5 is a graph of % active anion released v the amount of sodiumcarbonate, for sodium lauryl sulfate (SLS) surfactant;

FIG. 6 is a graph of % active anion released v the amount of sodiumcarbonate, for lecithin surfactant;

FIG. 7 is a graph of % active anion released v the amount of sodiumcarbonate, for poloxamer 407;

FIG. 8 is a bar graph showing % solubility v amount of sodium laurylsulfate (SLS) surfactant;

FIG. 9 is a bar graph showing % solubility v amount of lecithinsurfactant;

FIG. 10 is a bar graph showing % solubility v amount of poloxamer 407surfactant;

FIG. 11 is a bar graph showing % released v amount of sodium laurylsulfate (SLS) surfactant;

FIG. 12 is a bar graph showing % released v amount of lecithinsurfactant;

FIG. 13 is a bar graph showing % released v amount of poloxamer 407surfactant;

FIG. 14 is a graph showing the % solubility for 0 mg surfactant v amountof sodium carbonate;

FIG. 15 is a graph showing % release for 0 mg surfactant v amount ofsodium carbonate;

FIG. 16 is a graph showing the % solubility for 50 mg surfactant vamount of sodium carbonate;

FIG. 17 is a graph showing % release for 50 mg surfactant v amount ofsodium carbonate;

FIG. 18 is a graph showing the % solubility for 100 mg surfactant vamount of sodium carbonate;

FIG. 19 is a graph showing % release for 100 mg surfactant v amount ofsodium carbonate;

FIG. 20 is a graph showing the % solubility for 200 mg surfactant vamount of sodium carbonate;

FIG. 21 is a graph showing % release for 200 mg surfactant v amount ofsodium carbonate;

FIG. 22 is a graph showing pH v % solubility in sodium lauryl sulfate(SLS) with sodium carbonate;

FIG. 23 is a graph showing pH % release in sodium lauryl sulfate (SLS)with sodium carbonate;

FIG. 24 is a graph showing pH v % solubility in lecithin with sodiumcarbonate;

FIG. 25 is a graph showing pH % release in lecithin with sodiumcarbonate;

FIG. 26 is a graph showing pH v % solubility in poloxamer 407 withsodium carbonate;

FIG. 27 is a graph showing pH % release in poloxamer 407 with sodiumcarbonate;

FIG. 28 is a table of the % solubility and % release results obtained inExperiment 4; and

FIG. 29 is a table of the % solubility and % release results obtained inExperiment 5.

DETAILED DESCRIPTION Experiment 1—Comparing the In Vitro and In VivoRate of Release of 400 mg Ibuprofen from LDH-Ibuprofen Tablet Againstthe Rate of Release of Ibuprofen from Brufen®

The in vitro dissolution testing of the rate of release of ibuprofenfrom a tablet formulation of LDH-ibuprofen (400 mg ibuprofen) comparedagainst rate of release of ibuprofen from Brufen®, a commerciallyavailable tablet formulation containing 400 mg ibuprofen, showedcomparable release of >95% after 5 minutes.

However, in a clinical study to compare the Pharmacokinetic (PK)performance of a tablet formulation of LDH-ibuprofen (400 mg ibuprofen)against the performance of Brufen®, a commercially available tabletformulation containing 400 mg ibuprofen, the LDH-ibuprofen tablet failedto show bioequivalence to the Brufen® product. As illustrated in FIG. 1,the PK results show comparable AUC and time to maximum plasmaconcentration (Tmax). The rapid ibuprofen absorption in the first hourin the stomach for the LDH-ibuprofen tablet is comparable with the rateof absorption for Brufen®. Following this however, a slower moreprolonged ibuprofen release from the LDH-ibuprofen tablet is observed asthe remaining ibuprofen ion-exchanges out of the LDH matrix as ittravels down the GI tract. This results in a C_(max) for theLDH-ibuprofen tablet being reduced to 65% of that observed with Brufen®.

The differences between the in vitro and in vivo results may be due tothe use of a phosphate buffer in the in vitro dissolution testing whichmay be promoting ion-exchange. This theory was tested and is apparentlyconfirmed as different release rates are obtained depending on whichbuffer is used and at what concentration. In addition, dissolutiontesting using FaSSIF and FeSSIF buffers (maleate buffers which are morereflective of the stomach and intestines) showed that these buffers haveinsufficient buffering capacity to promote ion exchange and hence sloweddown the release of the drug from the LDH matrix.

Experiment 2: Testing Different Agents on LDH-Ibuprofen to Determinetheir Effect on The Amount Of Ibuprofen Dissolved ExperimentalConditions

400 mg LDH-ibuprofen (equivalent to 200 mg ibuprofen) is added to 0.05Mhydrochloric acid (50 ml) with various agents to test their effect inany on the rate of ibuprofen release. The mixture is stirred for 15minutes and then sampled HPLC for analysis.

TABLE 1 AGENT @ 100 mg AGENT @ 300 mg DIS- DIS- SOLVED mg/ SOLVED mg/AGENT pH (%) mL pH (%) mL NONE 2.0 1 0.04 6.1 4 0.14 (CONTROL) MgCO₃ 2.62 0.06 — — — Na(CO₃)₂ 6.2 8 0.33 — — — NaHCO₃ 2.7 2 0.09 — — — CaCO₃ 2.51 0.05 3.6 2 0.08 Mg(OH)₂ 2.3 1 0.04 Na₂SO₄ 3.3 2 0.08 3.7 1 0.05 SodiumLauryl 4.3 1 0.03 5.3 48  1.91 Sulfate Ca₃(PO₄)₂, 3.2 1 0.04 3.7 1 0.05CaHPO₄ 3.2 1 0.03 3.6 1 0.03

Looking at the above results, there does not appear to be any linearrelationship between pH and solubility, e.g. 100 mg sodium carbonate and300 mg of magnesium carbonate each give a pH of approximately 6, butsodium carbonate dissolved about 8% ibuprofen, whereas magnesiumcarbonate only dissolved about 3.5% ibuprofen. Consequently, contrary tothe teaching in EP1341556B, the rate of ibuprofen release from the LDHlayers is not merely a matter of ensuring that the pH is at a particularlevel. Also, as the above results demonstrate, the addition of sodiumcarbonate surprisingly improves the rate of ibuprofen release to agreater extent than would be expected from the results obtained for thecarbonates disclosed in EP1341556B. The two calcium phosphate materials,although similar to the chemicals used in a phosphate buffer, gave poordissolution whereas adding the surface active agent sodium laurylsulfate dissolved the highest amount of ibuprofen at 47.6%.

The following two test methods have been developed to test the efficacyof the proposed modifier systems according to the present invention. Itis particularly instructive to use the two methods in parallel when themodifier system contains a combination of constituents which alter boththe solubility and the release of the ibuprofen:

1) Solvent System Method for Determining the Total Amount of IbuprofenReleased from the LDH

This method determines the total amount of ibuprofen that is releasedfrom the LDH matrix.

Method:

LDH-ibuprofen (200 mg dose of ibuprofen) and modifier agent (where used,in the amounts shown in Table 2), are added to 0.05M HCl (50 mL) and theresulting solution stirred for 15 minutes. After 15 minutes, methanol(50 mL) followed by a 1:1 mixture of methanol and water (150 mL) areadded to the stirred LDH-ibuprofen/HCl solution. A sample is thenremoved for analysis to determine the total amount of ibuprofen(dissolved and undissolved) which is released into the HCl solution.Further dilution is conducted as required.

2 Solubility Method For Determining The Amount Of Ibuprofen Dissolved

The solubility method determines how much of the free ibuprofendissolves in the acid medium. The medium is designed to reflect theconditions found in a fasted human stomach. The difference between theamount determined by method 1 and the amount determined by method 2 isthe amount of ibuprofen which formed as a precipitate.

LDH-ibuprofen (200 mg dose of ibuprofen) and modifier agent according tothe present invention (where used, in the amounts shown below in Table2), are added to 0.05M HCl (50 mL) and the resulting solution stirredfor 15 minutes. After 15 minutes, a sample is taken for analysis todetermine the amount of ibuprofen dissolved in the HCl solution. Furtherdilution is conducted if required with a standard diluent(acetonitrile:water).

TABLE 2 TOTAL AMOUNT OF IBUPROFEN RELEASED AMOUNT OF IBUPROFEN FROM THELDH AS DISSOLVED AS DETERMINED USING THE DETERMINED USING THE SAMPLESOLVENT METHOD SOLUBILITY METHOD Ibuprofen free acid 95% NegligibleLDH-ibuprofen + 300 mg 41% 26% Na₂CO₃ LDH-ibuprofen + 300 mg SLS 59% 48%

Experiment 3: Testing Modifier Systems According to the PresentInvention which Comprise a Range of Compounds with the General FormulaMA Together with a Range of Surfactants

A composition containing 400 mg LDH-ibuprofen (200 mg dose ofibuprofen), and a modifier system containing 200 mg of a compound withthe general formula MA and 200 mg of a surfactant, were mixed togetherand added to 0.05M HCl (50 mL) and the resulting solution stirred for 15minutes. Samples of the of the reaction solution were removed and usedto determine the amount of ibuprofen released by each of the modifiersystems using both the solvent system method and the solubility methoddescribed above. The results obtained are detailed below in Table 3a andTable 3b.

TABLE 3a Surfactant None Lecithin Poloxamer Sodium lauryl sulfateSolubility Solvent Solubility Solvent Solubility Solvent SolubilitySolvent Method Method Method Method Method Method Method Method Salt(200 mg) pH (%) (%) pH (%) (%) pH (%) (%) pH (%) (%) None 2.0 1 40Sodium carbonate 7.4 3 82 9.0 6 56 9.3 57 88 Sodium Bicarbonate 4.9 4 43Sodium sulfate 2.4 3 56 Sodium nitrate 2.1 4 64 Sodium dihydrogen 3.9 822 phosphate Sodium phosphate 7.3 30 99 Sodium hydroxide 12.1 33 63Sodium chloride 2.8 2 51 Disodium hydrogen 5.8 13 95 phosphate Sodiumcitrate 4.3 1 95 Magnesium carbonate 2.9 2 44 Aluminium carbonate 2.1 111 Calcium carbonate 4.9 0 26 Lithium citrate 5.6 14 94

TABLE 3b Surfactant Benzalkonium Diotadecyl-dimethylammonium chloridechloride Solubility Solvent Solubility Solvent Salt pH Method Method pHMethod Method Sodium 4.0 7 50 6.7 2 36 carbonate

As the results in Table 3a show, all of the modifier systems testedaffect (increase or decrease) the total amount of ibuprofen releasedand/or the amount of ibuprofen dissolved, and using this fact it ispossible to design a modifier system which will control the amount ofactive anion released and control the amount of active anion dissolvedin the acidic media of the stomach. The modifier system whichsignificantly increases the total amount of ibuprofen released fromLDH-ibuprofen, relative to the total amount of ibuprofen released fromLDH-ibuprofen in the absence of a modifier system, comprises 200 mglecithin and 200 mg of one of sodium carbonate, sodium phosphate,disodium hydrogen phosphate, sodium citrate, lithium carbonate andlithium citrate. A modifier system which comprises 200 mg sodium laurylsulfate and 200 mg sodium carbonate also significantly increases boththe total amount of ibuprofen released and the amount of ibuprofen whichdissolves. A modifier system which significantly decreases the totalamount of ibuprofen released from LDH-ibuprofen, relative to the totalamount of ibuprofen released from LDH-ibuprofen in the absence of amodifier system, comprises 200 mg lecithin and 200 mg of one of sodiumdihydrogen phosphate, aluminium carbonate and calcium carbonate.

Experiment 4: Determination of the Amount of Ibuprofen Released fromLDH-Ibuprofen Compositions by the Addition of Test Modifier SystemsAccording to the Present Invention (Sodium Carbonate and Surfactant) toan LDH-Ibuprofen Material

A composition containing 400 mg LDH-ibuprofen (200 mg dose ofibuprofen), sodium carbonate and a surfactant in different ratios weremixed together and added to 0.05M HCl (50 mL) and the resulting solutionstirred for 15 minutes. Samples of the of the reaction solution wereremoved and used to determine the amount of ibuprofen released by eachof the sodium carbonate/surface active agent combinations using both thesolvent system method and the solubility method described above. Theresults obtained are detailed in FIG. 28.

CONCLUSION

The results presented in FIG. 28 highlight many interesting features ofthe relationship between sodium carbonate and a surfactant, and theresulting effect this combination has on the % release of ibuprofen froman LDH matrix and the % solubility of the released ibuprofen in anacidic medium. Some of these features include:

The presence of sodium carbonate appears to provide a decrease in the %release of the ibuprofen (41% with sodium carbonate v 65% without sodiumcarbonate), but the amount of released ibuprofen which then dissolves inan acid medium is increased from 1% (when no sodium carbonate ispresent) to 25% (when 300 mg sodium carbonate is present).

For a particular amount of sodium carbonate, the total amount ofibuprofen released does not appear to be influenced by either the choiceof surfactant or the amount of surfactant (in the range 50 mg to 300mg). However, the choice of surfactant does appear to influence thesolubility of the released active anion and there is a wide variation in% solubility over the range of surfactants tested. This suggests thatnot all of the surfactants act to solubilise the released ibuprofen.Also the presence of sodium carbonate appears to act in a similar waywith all surfactants because (apart for a couple of exceptions 200 mgSodium Lauryl Sulfate (SLS) and 200 mg lecithin) the % release is of asimilar order of magnitude for a given level of sodium carbonate.

The addition of <100 mg sodium carbonate appears to cause a decrease inthe % release, relative to the % release observed for 0 mg sodiumcarbonate, whereas the addition of >100 mg sodium carbonate appears toincrease % release and with 200 mg sodium carbonate % release of 77 to88% is observed. This provides the benefit that the amount of ibuprofenrelease can be controlled, and not just increased, by using the modifiersystems of the present invention.

Experiment 5: Determination of the Amount of Active Anion Released fromLDH-Active Anion Compositions by the Addition of Test Modifier SystemsAccording to the Present Invention (Sodium Carbonate and Surfactant) toan LDH-Active Anion Material

This Experiment is analogous to Experiment 4 above except that it teststhe effect of the modifier systems according to the present invention(which comprise either lecithin or poloxamer in combination with sodiumcarbonate) on LDH-active anion materials, where the active anion iseither naproxen, ketorolac, diclofenac or atorvastatin.

A composition containing LDH-active anion (containing a 200 mg dose ofthe active anion), sodium carbonate and a surfactant in different ratioswere mixed together and added to 0.05M HCl (50 mL) and the resultingsolution stirred for 15 minutes. Samples of the reaction solution wereremoved and used to determine the amount of active anion released byeach of the sodium carbonate/surface active agent combinations usingboth the solvent system method and the solubility method describedabove. The results obtained are detailed in FIG. 29.

1. A composition comprising: i) one or more LDH-active anion materialscomprising an LDH matrix intercalated with one or more active anions,and ii) a modifier system comprising a) one or more surfactants, incombination with b) one or more compounds having the generic formula MA,where M comprises one or more positively charged ions and A comprisesone or more negatively charged counter ions.
 2. A composition accordingto claim 1 wherein the one or more surfactants are selected from anionicsurfactants, zwitterionic (amphoteric) surfactants, cationic surfactantsand non-ionic surfactants.
 3. A composition according to claim 2 whereinthe one or more surfactants are selected from sodium lauryl sulfate,lecithin and poloxamer.
 4. A composition according to claim 1 wherein Mcomprises the one or more positively charged ions selected from one ormore mono-, di-, or tri-valent metals.
 5. A composition according toclaim 4 wherein M comprises one or more metals selected from alkalimetals, alkaline earth metals and transition metals.
 6. A compositionaccording to claim 1 wherein the one or more negatively charged counterions, A, are selected from carbonate, hydrogen carbonate, sulfate,hydroxide, oxide, chloride, bromide, fluoride, nitrate, dihydrogenphosphate, hydrogen phosphate, phosphate, acetate, maleate, citrate,mesylate, tartrate, gluconate, formate, malate, oxylate, succinate,tosylate, fumarate, pamoate, furoate, propionate, saccharate andthiocyanate anions.
 7. A composition according to claim 1 wherein theone or more active anions are derived from ibuprofen, naproxen,ketorolac, diclofenac, indomethacin and atorvastatin, either in saltand/or free acid form.
 8. A composition according to claim 1 wherein themodifier system has a weight ratio of the LDH matrix:the one or morecompounds having the generic formula MA: the one or more surfactants, of2:0.1 to 4:0.1 to
 4. 9. A composition according to claim 1 comprising400 mg LDH-ibuprofen (contains 200 mg LDH), at least 100 mg sodiumcarbonate and 200 mg of one or more surfactants selected from sodiumlauryl sulfate, poloxamer and lecithin.
 10. A method for 1) controllingthe total amount of active anion released from the LDH matrix underacidic conditions designed to represent the conditions found in a fastedhuman stomach, and 2) controlling the amount of released active anionwhich is dissolved in the acidic medium, the method comprising the stepof forming a composition comprising: i) one or more LDH-active anionmaterials comprising an LDH matrix intercalated with one or more activeanions, and ii) a modifier system comprising a) one or more surfactants,in combination with b) one or more compounds having the generic formulaMA, where M comprises one or more positively charged ions and Acomprises one or more negatively charged counter ions, wherein theamount of released active anion which is dissolved in the acidic mediumis controlled relative to both the amount which is dissolved when theone or more surfactants is used in the absence of the metal salt and theamount which is dissolved when the one or more metal salts is used inthe absence of the one or more surfactants.
 11. A formulation comprisinga composition containing i) one or more LDH-active anion materials, andii) a modifier system comprising a) one or more surfactants, incombination with b) one or more compounds having the generic formula MA,where M comprises one or more positively charged ions and A comprisesone or more negatively charged counter ions.
 12. A formulation accordingto claim 11 in a form selected from dry granules, tablets, caplets,orally disintegrating tablets, orally disintegrating granules, lozenges,films, capsules, powders, effervescent formulations and buccal andsub-lingual formats.